Cancers of the central nervous system are the most common solid tumors arising within the pediatric population, and most children with brain tumors require radiotherapy as part of their treatment.

Unfortunately, delivery of radiotherapy to the pediatric brain is associated with numerous risks. These risks are present due to the proximity of tumors to vital structures within the brain and skull base, including the pituitary gland, cochlea, optic nerves, optic chiasm, brain stem, and spinal cord. Although efforts are ongoing to reduce radiation dose to these structures, complete avoidance is frequently impossible

Proton beam radiotherapy may allow improved dose distribution and precision because of steep dose fall-off beyond the Bragg peak, as well as the particulate nature of protons that allows improved dose conformality.

Data from proton centers around the world indicates that use of proton radiotherapy for treatment of pediatric brain tumors may allow improved sparing of organs at risk when compared to photon radiotherapy (MacDonald SM, IJROBP, 2008; Merchant TE, Pediatr Blood Cancer, 2008; Rutz HP, IJROBP, 2008); however, most studies have been performed in small populations with limited follow-up.

As the use of proton technology becomes more widespread, defining normal tissue tolerances is essential to facilitation of safe and effective treatment.

This study was carried out in order to describe the experience of treating children with central nervous system tumors, specifically chordoma, chondrosarcoma, and chondroma, with proton radiotherapy at the Institut Curie-Centre de Protonthérapie d’Orsay (ICPO) in Orsay, France.

Materials and Methods

This study considered 30 children who underwent post-operative radiotherapy with high-dose combination photon-proton or proton only radiotherapy between July 1996 and July 2006.

Pathologic diagnosis was chordoma for 26 patients, low grade chondrosarcoma for 3 patients, and chondroma for one patient.

Median patient age was 13.5 years (range 7 – 17 years).

One patient received chemotherapy prior to radiotherapy.

Target volumes were delineated to encompass the skull base alone in 16 cases, the upper spine alone in one case, and both the skull base and upper spine in 13 cases.

Combination photon-proton radiotherapy was utilized in treatment of 29 patients, and proton radiotherapy alone in treatment of one.

Patients were treated with horizontal fixed beam passively scattered proton irradiation, in either the seated or supine position.

Dose constraints were imposed in order to protect vital organs at risk for radiation-induced toxicity:

Optic chiasm: Maximum dose 59 CGE

Optic nerves: Maximum dose 60 CGE

Brainstem: Maximum dose 55 CGE on surface in close proximity to GTV, and 48 CGE elsewhere.

Cochlea: Maximum dose 55 CGE when in close proximity to GTV, and 50 CGE otherwise.

Temporal lobe: Maximum dose 60 CGE

Results

Median follow-up was three years (range 0.5 – 12 years). Seven patients were excluded from analysis because of either tumor progression or insufficient information.

Mean GTV dose for patients treated for chordomas was 69.2 CGE, and was 63.2 for those treated for chondrosarcomas.

Mean and maximum dose to vital structures were analyzed:

Mean Dose (CGE/ Gy)

Maximum Dose (CGE/ Gy)

Pituitary Gland

50

57

Optic Nerve

32

47

Optic chiasm

42

47

Cochlea

47

60

Brainstem

35

65

Cervical spinal cord

18

49

Side effects and late toxicities were scored retrospectively according to the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 3.0.

The incidence of grade 2 or greater toxicity was less than 10%, and that of grade 3 toxicity was less than 5%. When pre-irradiation toxicities were subtracted, incidence of new grade 2 or greater toxicity was less than 0.5%.

Four patients developed neurologic toxicity: Two experienced cranial nerve XII deficits, one experienced a seizure, and one developed temporal lobe enhancement on further imaging without clinical symptoms.

One patient developed grade 4 visual deterioration.

Sensorineural hearing loss was experienced by two children (one bilateral, one unilateral).

Two patients developed symptomatic neck fibrosis.

One patient developed meningioma.

Some degree of hypothalamic and/ or pituitary failure developed in 30% of patients.

Author's Conclusions

The authors conclude that delivery of fractionated proton radiotherapy in excess of 60 CGE is feasible for children over five years of age, and that this treatment appears safe.

They note that visual and auditory toxicities occurred in less than 5% of children treated according to the method described, and that pituitary failure (partial, in most cases) occurred in approximately 30%.

They note that their results should be interpreted in the context of delivery of precise radiotherapy without systemic chemotherapy.

Clinical/Scientific Implications

As use of proton radiotherapy increases worldwide, defining dose-volume parameters for organs at risk for radiation toxicity is very important. Improved understanding of normal tissue tolerances will allow patients to receive the highest tolerated radiotherapy doses, theoretically increasing tumor control, while being treated safely with low risk of serious toxicity.

These issues are of paramount importance when considering treatment of pediatric brain tumors, as risk of severe toxicity secondary to radiation of the developing brain and nearby structures is well-recognized.

The authors of this study describe a series of patients treated within a single institution. Although the cohort of patients described is rather small, some patients within this study have been followed for 12 years. Given the small amount of data published regarding use of proton radiotherapy in treatment of pediatric patients, this study will be of value to centers establishing programs for treatment of pediatric brain and skull base tumors.

Longer follow-up and future updates of this patient population will be of interest, as this group of patients will remain amongst those with the longest follow-up after proton irradiation. Late effects are recognized to develop many years after completion of radiotherapy, particularly in the pediatric population.

Several further analyses of the data presented here would be of interest:

Presentation of the dose-volume relationships for organs at risk, specifically for those patients who developed toxicity, would be of interest. Further understanding of dose received by specific organs at risk would be useful in future attempts to reduce toxicity even more.

Neurocognitive decline is perhaps the most recognized side-effect of radiation to the pediatric brain. Analysis of neurocognitive effects in this population would be of great interest.

As the authors note, this data should be considered in the context of treatment of children over 5 years old, and not receiving chemotherapy. Toxicities are well-recognized to be potentially more severe in younger children, and these data should not be extrapolated to the younger population. Additionally, certain chemotherapies may contribute to late-effects risk and require dose reduction to certain organs at risk (the cochlea in the setting of cisplatin use, for example).

The data presented here are a valuable contribution to patient care, and will serve the radiation oncology community well as use of protons for treatment of pediatric brain malignancies expands. The authors demonstrate safe dosing parameters with relatively low risk of severe toxicity. Trials in larger populations with longer follow-up will be of interest as these become possible.